1. Field of the Invention
The present invention relates to a series of substituted aza-indole compounds. More specifically, the present invention relates to a novel series of N,2,3-substituted aza-indole derivatives. This invention also relates to methods of making these compounds. The compounds of this invention are inhibitors of poly(adenosine 5′-diphosphate ribose) polymerase (PARP) and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases including diseases associated with the central nervous system and cardiovascular disorders.
2. Description of the Art
Poly(adenosine 5′-diphosphate ribose) polymerase [poly(ADP-ribose) polymerase, PARP, EC 2.4.2.30] also known as poly(ADP-ribose) synthetase (PARS) is a chromatin-bound nuclear enzyme of eukaryotic cells, present at about 2×105 molecules/nucleus. The high degree of evolutionary conservation of PARP in multicellular organisms can be taken as an indication of the physiological importance of poly(ADP-ribosyl)ation. Activated by DNA strand breaks PARP transfers ADP-ribose units from NAD+ to nuclear proteins including histones and PARP itself. This reaction generates poly(ADP) ribose and nicotinamide, with the latter being a negative feedback inhibitor of PARP. The role of NAD+ in this sequence is distinct from its role as a redox cofactor in other enzymatic processes. The poly(ADP-ribose) thus formed typically contains in the order of 200 ribose units having linear and branched connections with one branch approximately every 25 units of ADP-ribose. The links are by α-(1″-2′)ribosyl-glycosic bonds. Because of the negative charges of ADP-ribose polymers, poly(ADP-ribosylated)proteins lose their affinity for DNA and are, therefore, inactivated. Poly(ADP-ribosyl)ation is an immediate, covalent, but transient post-translational modification. Poly(ADP-ribose) is in a dynamic state, its rapid synthesis being followed by a degradation catalyzed by the enzyme poly(ADP) glycohydrolase (PARG). Thus, PARP and other modified proteins are returned to their native state. For reviews on PARP see: Liadet. L., “Poly(adenosine 5′-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness”; Current Opinions Clin. Nutrition Metabolic Care, 5, 175-184 (2002). Burkle, A., “Physiology and pathophysiology of poly(ADP-ribosyl)ation”; BioEssays, 23, 795-806 (2001). Hageman, G. J. and Stierum, R. H., “Niacin, Poly(ADP-ribose) polymerse-1 and genomic stability”; Mutation Res., 475, 45-56 (2001). Smith, S., “The world according to PARP”; Trends Biochem Sci., 26, 174-179 (2001). Tong, W.-M. et al., Poly(ADP-ribose) polymerase: a guardian angel protecting the genome and suppressing tumorigenisis”; Biochim. Biophys. Acta, 1552, 27-37 (2001).
In cerebral ischemia, calcium influx into neurons causes the activation of nitric oxide synthase, leading to production of nitric oxide and subsequently the reactive radical peroxynitrite. Peroxynitrite causes extensive damage to DNA and results in uncontrolled activation of PARP. Cellular NAD and ATP are quickly used up and the cell dies a necrotic death due to loss of the source of cellular energy. DNA is similarly damaged by peroxynitrite in myocardial ischemia and in inflammation.
Several studies with PARP −/− animals and with a variety of inhibitors support the role of PARP in the pathophysiology of a number of disease models. In a stroke model, for example, the infarct size in PARP-deficient animals is 80% smaller compared to control PARP +/+ animals. See, for example, Eliasson, M. J. L. et al., “Poly(ADP-ribose)polymerase gene disruption renders mice resistant to cerebral ischemia”; Nature Med., 3, 1089 (1997). In addition, many studies using various PARP inhibitors (e.g. 3-aminobenzamide, GPI 6150, PJ-34 and nicotinamide) have shown reduction in stroke-induced infarction volume and reduced behavioral deficits in post-stroke treatment paradigms. See, generally, Takahashi, K. et al., “Post-treatment with an inhibitor of poly(ADP-ribose) polymerase attenuates cerebral damage in focal ischemia”; Brain Res., 829, 46, (1999). Mokudai, T. et al., “Delayed treatment with nicotinamide (vitamin B3) improves neurological outcome and reduces infarct volume after transient focal ischemia in Wistar rats”; Stroke, 31, 1679 (2000). Abdelkarim, G. E. et al., “Protective effects of PJ34, a novel, potent inhibitor of poly(ADP ribose) polymerase (PARP) in vitro and in vivo models of stroke”; Int. J. Mol. Med., 7, 255 (2000). Ding, Y. et al., “Long-term neuroprotective effect of inhibiting poly(ADP-ribose) polymerase in rats with middle cerebral artery occlusion using a behavioral assessment”; Brain Res., 915, 210 (2001).
Other disease models in which the role of PARP has been established by using inhibitors or the knockout are streptozocin-induced diabetes (see, Mabley, J. G. et al., “Inhibition of poly(ADP-ribose) synthetase by gene disruption or inhibition with 5-iodo-6-amino-1,2-benzopyrone protects mice from multiple-low-dose-streptozotocin-induced diabetes”; Br. J. Pharmacol., 133, 909-919 (2001); Gale, E. A. et al., “Molecular mechanisms of beta-cell destruction in IDDM: the role of nicotinamide”; Horm. Res., 45, 39-43 (1996); and Heller, B. et al., “Inactivation of the poly(ADP-ribose) polymerase gene affects oxygen radical and nitric oxide toxicity in islet cells”; J. Biol. Chem., 270, 11176-11180 (1995).
The PARP is also implicated in diabetic cardiomyopathy, see, Pacher, P. et al., “The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes”; Diabetes, 51, 514-521 (2002); and in head trauma, see, LaPlaca, M. C. et al., “Pharmacological inhibition of poly(ADP-ribose) polymerase is neuroprotective following traumatic brain injury in rats”; J. Neurotrauma, 18, 369-376 (2001). Also see, Verma, A., “Opportunities for neuroprotection in traumatic brain injury”; J. Head Trauma Rehabil., 15, 1149-1161 (2000).
Further diseases involving PARP include myocardial ischemia, see generally, Pieper, A. A. et al., “Myocardial postischemic injury is reduced by poly(ADP-ribose) polymerase-1 gene disruption”; Mol. Med., 6, 271-282 (2000). Also see, Grupp, I. L. et al., “Protection against hypoxia reoxygenation in the absence of poly(ADP-ribose) synthetase in isolated working hearts”; J. Mol. Cell. Cardio., 31, 297-303 (1999).
Additional diseases include experimental allergic encephalomyelitis (EAE), see for example, Scott, G. S. et al., “Role of poly(ADP-ribose) synthetase activation in the development of experimental allergic encephalomyelitis”; J. Neuroimmunology, 117, 78-86 (2001).
It has also been reported that cancer may be caused due to the effects of PARP, see for example, Martin, N. M., “DNA repair inhibition and cancer therapy”; J. Photochem. Photobiol. B. 63, 162-170 (2001). Finally, aging related diseases also have been implicated due to PARP, see Von Zglinicki, T. et al., “Stress, DNA damage and aging—an integrative approach”; Exp. Geront., 36, 1049-1062 (2001). Also see, Rosenthal, D. S. et al., “Poly(ADP-ribose) polymerase and aging”; in “The role of DNA damage and repair in aging”, Gilchrist, B. A. and Bohr, V. A., eds., Elsevier Science B. V. (2001), pp 113-133.
All of the references described herein are incorporated herein by reference in their entirety.
It is an object of this invention to provide a series of substituted indole derivatives which are potent, selective inhibitors of PARP-1.
It is also an object of this invention to provide processes for the preparation of the substituted indole derivatives as disclosed herein.
It is further an object of this invention to provide a series of novel indole-3-carboxaldehydes that are potent inhibitors of PARP-1 enzyme as demonstrated by their activity against the enzyme in vitro and in a whole cell assay.